Project Summary In United States, there are ~130,000 new cases and ~50,000 deaths caused by colorectal cancer (CRC) every year, making CRC a serious health problem. There is an urgent need to identify novel therapeutic target of CRC, in order to develop targeted strategies for prevention and/or treatment of CRC. The objective of this proposal is to validate the roles of cytochrome P450 (CYP) epoxygenases (largely CYP2C and CYP2J isoforms) in CRC, in order to establish these enzymes as a novel therapeutic target of CRC. CYP epoxygenases catalyze the oxidative metabolism of polyunsaturated fatty acids to fatty acid epoxides, which are endogenous lipid signaling molecules involved in regulation of inflammation and hemostasis. To date, the roles of CYP epoxygenases and their metabolites in cancer are poorly characterized, and their roles in CRC are completely unknown. In our work in progress, we discovered that the expressions of CYP epoxygenases and their metabolites were dramatically increased in cell culture model, animal model, and human cancer patients of CRC; in addition, pharmacological inhibition of CYP epoxygenases suppressed CRC in mice, suggesting that the previously unappreciated CYP epoxygenase pathway could play critical roles in CRC. In this proposal, we will test hypothesis that CYP epoxygenases and their metabolites epoxyoctadecenoic acids (EpOMEs) increase colorectal cancer (CRC). To test this hypothesis, we propose two specific aims: (1) use Cyp2c gene cluster knockout mouse to validate the roles of CYP epoxygenases in CRC, and (2) determine the effects and mechanisms of EpOMEs on CRC in vitro and in vivo. The outcome of this R03 grant is to lay the foundation to further investigate the roles of CYP epoxygenase pathway in CRC, in order to develop CYP epoxygenases as a novel therapeutic target of CRC, and CYP metabolites (such as EpOMEs) as potential biomarkers of CRC.